The use of topical products in the treatment of the mucocutaneous Herpes simplex in immunocompetent patients is currently restricted to the utilization of antiviral drugs which inhibit the DNA polymerase in the cells infected by the virus, preventing its replication. Among the aforementioned antiviral drugs, the most important is the acyclovir family (pencyclovir, gancyclovir, valacyclovir); however, in some cases idoxuridine, trifluorotimidine, vidarabine and foscamet are indicated. In topical applications, acyclovir toxicity is particularly observed in cases of hypersensitivity. Furthermore, when systemically administering antiviral drugs, adverse reactions are frequent occurrences. Topical anti-inflammatory drugs can also be used as adjuvant agents in the treatment. It should be observed that in the conventional herpes treatment which is under discussion here, the drugs have a synthetic origin and their basic activity is antimicrobial.
The pertinent literature explains that the manifestations of recurrent lip herpes occur in 20-45% of the population, and that, regardless of ethnic group or geographic region, approximately 70% of over 40-year-olds have antibodies against the type 1 HSV virus. The recurrence frequency among the affected individuals varies from rare episodes up to 12 recurrences or more per year. After the primary infection, which usually occurs in childhood, the virus establishes a latent infection in the trigeminal ganglions. In immunocompetent individuals, the reactivations represent episodes of limited replication, disappearing in 10 days or so, regardless of any treatment. At this stage, however, the release of infecting viral particles occurs, and they are likely to be contagious. The increasing use of topical antiviral drugs with activity on the DNA polymerase, such as the nucleoside analogs (acyclovir and pencyclovir), has been regarded as a reference for comparative studies. Although the reference treatment is generally safe, its clinical efficacy is limited, and there is an increasing concern about the emergence of a viral resistance due to the disseminated use of such cytostatic drugs, particularly in populations of immunocompromised individuals. Forecasts derived from mathematical models suggest that the increasing utilization of nucleoside analogs may raise the prevalence of resistant viral forms from the current 0.3% to 1.5-3.0% in the next 50 years. This possibility could represent an exponentially increasing dissemination of resistant viral forms. On the other hand, the topical drug anti-inflammatory activity itself helps to decrease the viral spreading by decreasing the intensity and duration of the symptoms of the active stage, in which the infection is likely to occur.
Among the most recent approaches to the treatment of inflammations caused by the herpes virus, phytotherapy, also referred to as herbal medicine, has been increasingly employed. One of the most promising plants is Uncaria tomentosa, colloquially known as “unha de gato” in Brazil, and, in other countries, as cat's claw, una de gato, paraguayo, garabato, garabato casha, samento, toron, tambor huasca, una huasca, una de gavilan, hawk's claw, saventaro.
The Uncaria tomentosa portions most used for phytotherapic purposes are the bark, roots and leaves. The traditional methods of manipulation of these portions for obtaining their therapeutically active components involve grinding, coction and extraction by means of solvent substances, with an optional heating.
Uncaria tomentosa belongs to the Rubiaceae family, formed by the main species U. tomentosa and U. guianensis. It has been used for centuries by Indians and the Amazonian forest populations for treating asthma, inflammations of the urinary tract, postpartum recovery, kidney infections, arthritis, rheumatism, gastric ulcers, cancer, and diabetes, among other illnesses. This fact suggests that U. tomentosa contains a wide range of therapeutic and prophylactic components. In relatively recent years the ethnologist Klaus Keplinger offered a decisive contribution for the elucidation of the U. tomentosa compound and its potential strength as a phytotherapic agent, inclusively for the treatment of cancer and AIDS, according to the patents U.S. Pat. No. 4,844,901, U.S. Pat. No. 4,940,725, U.S. Pat. No. 5,302,611, and U.S. Pat. No. 5,723,625. Keplinger's work has been amplified by contributions from other researchers, who have taken ahead the task of elucidating the components' potential phytotherapic activity and determining how they can be put to use.
The chemical compound of U. tomentosa includes 17 different alkaloids, glycosides of the quinovic acid, tannins, flavonoids, steroid fractions, including sitosterol, sigmasterol and carpesterol, triterpenes and other compounds (Sentore A, Cataldo A, Iaccarino F, et al. Phytochemnical and biological research on Uncaria tomentosa L. Boll Soc Ital Biol Sper 1989; 65:517-520). The “James Duke's Phytochemnical and Ethnobotanical” database presents a list of 29 chemical constituents present in Uncaria tomentosa (Beckstrom-Sternberg S, Duke J, Wain K. Chemicals in: Uncaria tomentosa DC (Pedaliaceae). 1994: The Ethnobotany Database, Agricultural Research Service). The following active constituents are particularly notable: the tetracyclic oxindole alkaloids (TOAs), represented by the compounds rynchophylline, isorynchophylline, corynoxeine, and isocorynoxeine (Keplinger et al., 1999 (Keplinger K, Laus G, Wurm M, et al. Uncaria tomentosa (Willd.) DC-Ethnomedicinal use and new pharmacological, toxicological and botanical results. J Ethnopharmacol 1999; 64:23-34); Laus G, Brossiner D, Keplinger K. Alkaloids of Peruvian Uncaria tomentosa. Phytochemistry; 45(4):855-860), 1997); Wagner H, Kreutzkamp B, Jurcic K. The alkaloids of Uncaria tomentosa and their phagocytosis-stimulating action [in German]. Planta Med 1985b October; (5):419-23). The most frequently investigated active constituents, which present immunomodulator and anti-inflammatory effects, are the pentacyclic oxindole alkaloids (PDAs). The already characterized POAs are: pteropodine, uncarine C, isopteropodine, uncarine E, speciophylline, uncarine F, Mitraphyllinee, and isoMitraphyllineee (Muhammad et al., 2001a (Muhammad I, Khan I A, Fischer N H, Fronczek F R. Two stereoisomeric pentacyclic oxindole alkaloids from Uncaria tomentosa: uncarine C and uncarine E. Acta Cryst 2001a; C57:240-2); Laus et al., 1997; Wagner et al., 1985b; Stuppner H, Sturm S, Konwalinka G. HPLC analysis of the main oxindole alkaloids of Uncaria tomentosa. Chromatographia 1992; 34:597-600).
Uncaria tomentosa has got two chemotypes: (1) the pentacyclic alkaloids type, and (2) the tetracyclic alkaloids type. The first one, which contains pentacyclic oxindole alkaloids (PDAs), is regarded by some researchers as the most active component of the cat's claw plant and contains just a few—or even none—tetracyclic oxindole alkaloids (TOAs). The second chemotype contains predominantly TOAs, both with no POAs at all and with a considerable amount of POAs. The TOAs are believed to be POAs antagonists on what concerns to the POAs' desirable effects, and, therefore, it is important to tell the two chemotypes from one another (Wurm M, Kacani L, Laus G, Keplinger K, Dierich M. Pentacyclic oxindole alkaloids from Uncaria tomentosa induce human endothelial cells to release a lymphocyte-proliferation-regulating factor. Planta Med 1998; 64:701-704).
Thus, the determination of the chemotype is crucially important in the plant's analysis and processing, with the purpose of obtaining a pharmaceutical preparation. This is due to the fact that the pentacyclic and tetracyclic alkaloids possess different activity mechanisms, and as previously mentioned, they may even be antagonists to each other (Keplinger, K., Laus, G., Wurm, M. et col.: Uncaria tomentosa (Willd.) DC. —ethnomedicinal use and new pharmacological, toxicological and botanical results. J Ethnopharmacol, 1999, 64: 23-34; Reinhard K. H.: Uncaria tomentosa (Willd.) DC. —Cat's claw, Una de gato oder Katzenkralle. Z. Phytother, 1997, 18: 112-121).
The document FR 2824270 describes a process of preparation of a hydroalcoholic extract from Uncaria tomentosa (Example 1, b1-a), in which finely sectioned portions of the plant are subject to reflux, at a temperature of 65.degree. C., for 2 hours, in a 70% ethanol aqueous solution. This process presents some disadvantages, such as: (i) heating favors isomerization and other alterations in the physical-chemical characteristics of the constituents found in the in natura plant, and (ii) the chemical non-characterization and non-standardization of the extract obtained prevents the control of the final product's therapeutic activity. As a matter of fact, the compound described in the document FR 2824270 has got a predominantly cosmetic purpose.
Pharmacological studies have shown that the pentacyclic oxindole alkaloids, active constituents of the herbal extract of the plant Uncaria tomentosa (Willd) DC Rubiaceae, present immunomodulator anti-inflammatory, antioxidant and cytoprotective activities. The quinovic acid glycosides present in Uncaria tomentosa have been tested in cell cultures (CER and HeLa), showing antiviral and anti-inflammatory activity. The mutagenic and antimutagenic potential of Uncaria tomentosa presents antimutagenic activity in photomutagenic systems in vitro and absence of mutagenic effect in Salmonella typhimurium. Experimentally, Uncaria tomentosa could offer protection against a whole range of oxidative stresses, including the peroxynitrite, which has been implied as a mediator in the arthritis inflammation and other chronic inflammatory diseases, as well as against the cytotoxicity induced by UV rays and free radicals. The anti-inflammatory effect of Uncaria tomentosa results from its ability of inhibiting the production of TNF-alfa in vitro and in vivo and, in a smaller extent, of PGE2, both of them mediators of the inflammatory processes. The expression of the NF-kappaB transcription factor, which regulates the transcription of several genes involved in the inflammatory process, is reduced in vitro by Uncaria tomentosa extracts. On the other hand, its immunomodulator effect has been attributed to the increase in the lymphocites' proliferative ability, the stimulation of the phagocitary activity and the increase in the IL-1 and IL-6 production. Studies of the preclinical toxicity of the Uncaria tomentosa extracts have not shown any toxicity in vitro in concentrations up to 100 mg/ml.
Two tests (uncontrolled; unpublished results) with the extract of U. tomentosa-POA in topical preparations to be used in lesions caused by Herpes simplex and Varicela zoster have been performed, with better outcomes and with no adverse side effects (Immodal Pharmaka. Krallendorn® Uncaria tomentosa (Willd.) DC Root Extract: Information for Physicians and Dispensing Chemists. 3rd revised ed. Volders, Austria:Immodal; 1995. Available on request from immodal@volders.netwing.at. Immodal Pharmaka. Radix Uncariae tomentosae (Willd.) DC., pentacyclic chemotype (Krallendorn®): summarized research. Volders, Austria; Immodal. 2002. Immodal Pharmaka. Summary and assessment of clinical examinations of Krallendorn® products. Volders, Austria: Immodal, 1999a, Available on request from immodal@volders.netwing.at.; Immodal Pharmaka. Summary and assessment of: Pharmacodynamical examinations of extracts of Uncaria tomentosa (Willd.) DC. mod. pent. Volders, Austria: Immodal; 1999b).
In Western Europe the U. tomentosa extracts are used in daily doses of approximately 20-60 mg of the dry extract. The POAs are poorly soluble in water and well soluble in acids and alcohols; therefore, the U. tomentosa extracts are prepared in the form of 50% hydroalcoholic tinctures. In Germany and Austria the U. tomentosa extract in the form of a standardized powder is used two or three times a day in doses of 20-60 mg. Also in those two countries the preparations made from U. tomentosa roots are used mainly in disorders of the immune system (including allergies and rheumatoid arthritis) and as a supportive therapy to the treatment of cancer (to alleviate the consequences of chemotherapy and radiotherapy), as well as an adjuvant in viral infections with herpes or retroviruses as the HIV (Falkiewicz, B., ukasiak, J. “Vilcacora [Uncaria tomentosa (Willd.) DC. and Uncaria guianensis (Aublet) Gmell.]—a review of published scientific literature. Case Rep Clin Pract Rev, 2001: 2(4): 305-316).
In the United States market 4 types of Uncaria products are commercialized by 3 different manufacturers: (1) hydroalcoholic extract from U. tomentosa standardized for POAs; (2) aqueous extract from U. tomentosa standardized for CAES; (3) aqueous extract from Uncaria guianensis and (4) a relatively generic cat's claw product (usually labeled as UT), made from the plant's bark and roots, both in form of powder for capsules and tablets and finely sliced to be used in the form of tea (CAT′S CLAW (VINCARIA) Uncaria tomentosa (Willd.) DC.; Uncaria guianensis (Aubl.) Gmel. [Fam. Rubiaceae]-Overview; available in the Web in (http://www.sunrisewd.com/products/catsclawarticle.htm).
Although processes of extraction of pharmaceutically active components, including the hydroalcoholic extraction of U. tomentosa are already known, and, in addition to that, products designed for the treatment of herpes exist in the market, such products do not totally comply with the requisites of a satisfactory relief of the pain associated with the inflammation caused by the herpes virus and of a satisfactory bioavailability (for instance, a sufficient topical absorption) of the active components of U. tomentosa, especially the POAs.